Abordagem PK-PD do propofol na revascularização do miocárdio para estudo da influência da circulação extracorpórea na ligação às proteínas plasmáticas e no efeito hipnótico / PK-PD Model to investigate the free propofol plasma levels versus the hypnotic drug effect in patients undergoing coronary artery bypass grafting concerning the influence of CPB-hypothermia on drug plasma binding

Durante a cirurgia de revascularização do miocárdio com circulação extracorpórea e hipotermia (CEC-H) ocorre alteração na efetividade do propofol e na sua farmacocinética realizada a partir das concentrações plasmáticas do propofol total no decurso do tempo. A ligação do propofol à proteína plasmática parece estar alterada em consequência de diversos fatores incluindo a hemodiluição e a heparinização que ocorre no início da circulação extracorpórea, uma vez que se reportou anteriormente que a concentração plasmática do propofol livre aumentou durante a realização da circulação extracorpórea normotérmica. Por outro lado, a infusão alvo controlada é recomendada para manter a concentração plasmática do propofol equivalente ao alvo de 2 µg/mL durante a intervenção cirúrgica com CEC-H. Se alterações significativas na hipnose do propofol ocorrem nesses pacientes, então o efeito aumentado desse agente hipnótico poderia estar relacionado à redução na extensão da ligação do fármaco as proteínas plasmáticas; entretanto, o assunto ainda permanece em discussão e necessita de investigações adicionais. Assim, o objetivo do estudo foi investigar as concentrações plasmáticas de propofol livre em pacientes durante a revascularização do miocárdio com e sem o procedimento de CEC-H através da abordagem PK-PD. Dezenove pacientes foram alocados e estratificados para realização de cirurgia de revascularização do miocárdio com circulação extracorpórea (CEC-H, n=10) ou sem circulação extracorpórea (NCEC, n=9). Os pacientes foram anestesiados com sufentanil e propofol alvo de 2 µg/mL. Realizou-se coleta seriada de sangue para estudo farmacocinético e o efeito foi monitorado através do índice bispectral (BIS) para medida da profundidade da hipnose no período desde a indução da anestesia até 12 horas após o término da infusão de propofol, em intervalos de tempo pré-determinados no protocolo de estudo. As concentrações plasmáticas foram determinadas através de método bioanalítico pela técnica de cromatografia líquida de alta eficiência. A farmacocinética foi investigada a partir da aplicação do modelo aberto de dois compartimentos, PK Solutions v. 2. A análise PK-PD foi realizada no Graph Pad Prisma v.5.0 após a escolha do modelo do efeito máximo (EMAX sigmóide, slope variável). Os dados foram analisados utilizando o Prisma v. 5.0, p<0,05, significância estatística. As concentrações plasmáticas de propofol total foram comparáveis nos dois grupos (CEC-H e NCEC); entretanto o grupo CEC-H evidenciou aumento na concentração do propofol livre de 2 a 5 vezes em função da redução na ligação do fármaco às proteínas plasmáticas. A farmacocinética do propofol livre mostrou diferença significativa entre os grupos no processo de distribuição pelo prolongamento da meia vida e aumento do volume aparente, e no processo de eliminação em função do aumento na depuração plasmática e redução na meia vida biológica no grupo CEC-H. A escolha do modelo EMAX sigmóide, slope variável foi adequada uma vez que se evidenciou alta correlação entre os valores do índice bispectral e as concentrações plasmáticas do propofol livre (r2>0.90, P<0.001) para os pacientes investigados

During coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB) profound changes occur on propofol effect and on kinetic disposition related to total drug plasma measurements in these patients. It was reported that drug plasma binding could be altered as a consequence of hemodilution and heparinization before starts CPB since free propofol plasma levels was increased by twice under normothermic procedure. In addition, the target controlled infusion (TCI) is recommended to maintain propofol plasma concentration (2 µg/mL) during CABG CPB-H intervention. However, whether significant changes that occur in propofol hypnosis in these patients could be related to the reduction on the extension of drug plasma binding remain unclear and under discussion until now. Then, the objective of this study was to investigate propofol free plasma levels in patients undergoing CABG with and without CPB by a pharmacokinetics-pharmacodynamics (PK-PD) approach. Nineteen patients were scheduled for on-pump coronary artery bypass grafting (CABG-CPB, n=10) or off-pump coronary artery bypass grafting (OPCABG, n=9) were anesthetized with sufentanil and propofol TCI (2 µg/mL). Blood samples were collected for drug plasma measurements and BIS were applied to access the depth of hypnosis from the induction of anesthesia up to 12 hours after the end of propofol infusion, at predetermined intervals. Plasma drug concentrations were measured using high-performance liquid chromatography, followed by a propofol pharmacokinetic analysis based on two compartment open model, PK Solutions v.2; PK-PD analysis was performed by applying EMAX model, sigmoid shape-variable slope and data were analyzed using Prisma v. 5.0, considering p<0.05 as significant difference between groups. The total propofol plasma concentrations were comparable in both groups during CABG; however it was shown in CPB-group significant increases in propofol free plasma concentration by twice to fivefold occur as a consequence of drug plasma protein binding reduced in these patients. Pharmacokinetics of free propofol in CPB-H group compared to OPCAB group based on two compartment open model was significantly different by the prolongation of distribution half-life, increases on plasma clearance, and biological half-life shortened. In addition, the kinetic disposition of propofol changes in a different manner considering free drug levels in the CPB-H group against OPCAB group as follows: prolongation of distribution half-life and increases on volume of distribution, remaining unchanged biological half-life in spite of plasma clearance increased. BIS values showed a strong correlation with free drug levels (r2>0.90, P<0.001) in CPB-H group and also in OPCAB group by the chosen EMAX model sigmoid shape-variable slope analyzed by GraphPad Prisma v.5.0

[ outcomes of redo-coronary artery bypass grafting]

Application of off-pump technique for reoperative coronary artery bypass grafting [Redo CABG] has been limited by technical difficulties, potentiation for embolism of athermanous debris from the involved grafts, resulting in myocardial infarction, and rapid hemodynamic deterioration. In this descriptive study from 2002, at Cardiac surgery Department of Emam Reza Hospital, a total of 77 consecutive patients underwent redo CABG [64 ONCAB and 13 OPCAB] The outcomes of off-pump [OPCAB] and on-pump [ONCAB] redo CABG were compared. Surgical technique in 2 patients [%11] was converted from OPCAB to ONCAB due to hemodynamic instability, severe adhesion or graft injury; and in one patient [%7] the conversion from ONCAB to OPCAB was for severe aorta calcification. Propensity matched comparison of the outcome of OPCAB with ONCAB for redo CABG showed that OPCAB was associated with significant reduction in postoperative complications, volume of blood transfusion and hospitalization length. OPCAB can be safely and effectively applied for reoperative CABG, in selected cases

Resultados de la revascularización miocárdica sin derivación cardiopulmonar en pacientes femeninas / Outcomes of off-pump coronary artery bypass grafting in females

BACKGROUND: Women have more risk factors for coronary bypass graft surgery such as diabetes, high blood pressure, obesity, heart failure and shorter height (less body surface), compared with men. However, off-pump coronary artery bypass grafting demonstrates more benefits in females because of lower mortality, fewer postoperative respiratory complications, shorter hospital stay and improved outcome index. METHODS: We designed a retrospective study from the clinical files of females who underwent off-pump coronary artery bypass graft surgery in our hospital. RESULTS: Significant differences were found between genders in mean age, body surface area, incidence of high blood pressure, unstable angina, left main coronary artery disease or its equivalent, urgent and emergency surgery in relation to preoperative variables. According to the operative variables, we observed significant differences only in incomplete coronary artery bypass grafting. Postoperatively, differences were found in the use of inotropic support, late extubation (>24 h), wound infections and postoperative death. Those differences were evident in the incidence of major and minor adverse outcomes, resulting in major morbidity and mortality in women (p = 0.049). CONCLUSIONS: Higher morbidity and mortality are shown in women than in men after analyzing major and minor adverse outcomes that were more frequent in women.